EP1405646A2 - Pharmaceutically acceptable salts of local anaesthetics with anti-inflammatory compounds and methods for preparing the same - Google Patents

Abstract

The present invention provides pharmaceutically acceptable salts having localanesthetic and anti-inflammatory activities. The preferred pharmaceutically acceptable salt isa diclofenac salt of lidocaine. Diclofenac is a non-steroidal anti-inflammatory drug("NSAID"). Lidocaine is a local anesthetic. Other NSAID (excluding the salicylic acidderivatives) can be used to replace diclofenac and/or other local anesthetics can be used toreplace lidocaine. The pharmaceutically acceptable salts are crystalline compounds, whichare distinctively different from either the NSAID alone or the local anesthetic alone, asindicated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA),High Performance Liquid Chromatography (HPLC) and Fourier-Transformed InfraredSpectroscopy (FTIR) analyses. These pharmaceutically acceptable salts are suitable for usein topical treatment or parenteral injection to treat patients with localized pain, includingmuscle pain, joint pain, pain associated with herpes infection, and wound pain (such assurgical wound, burn wound etc.).

Description

FIELD OF THE INVENTION

The present invention relates to a group of novel pharmaceutically acceptable salts,each containing local anesthetic and anti-inflammatory activities. The preferredpharmaceutical acceptable salt in this group is diclofenac salt of lidocaine. Diclofenac is anon-steroidal anti-inflammatory drug (NSAID). Lidocaine is a local anesthetic. OtherNSAID (excluding the salicylic acid derivatives) can be used to replace diclofenac and/orother local anesthetics can be used to replace lidocaine. The pharmaceutically acceptablesalts of the present invention are physically and chemically distinctively different from eitherthe NSAID alone or the local anesthetic alone. The pharmaceutically acceptable salts of thepresent invention are particularly suitable for use in topical treatment or parenteral injectionto treat patients with localized pain, including, but not limited to, muscle pain, joint pain,pain associated with herpes infection, and/or wound pain (such as surgical pain or burn pain).The present invention also relates to methods for making the pharmaceutically acceptablesalts.

BACKGROUND OF THE INVENTION

In the management of pain and discomfort, two kinds of drugs are widely used. Thefirst kind is local anesthetics. Local anesthetics reversibly block the impulse conductionalong nerves and other excitable membranes that primarily utilize sodium channels.Clinically, this action blocks the pain sensation from specific areas of the body.

Local anesthetics are weak bases. There are three major classes of local anesthetics,which are ester derivatives (such as cocaine, procine etc.), amide derivatives (such aslidocaine, bupivacaine etc.), and others (such as dyclonine, pramoxine etc.). For therapeuticapplication, local anesthetics are usually made available as salts for reasons of solubility andstability. In the body, they exist either as the uncharged base (i.e., "free base") or as a cation.

Local anesthetics generally consist of a lipophilic group (frequently an aromatic ring)connected by an intermediate chain (commonly including an ester or amide) to an ionizablegroup (usually a tertiary amine). Optimal activity requires a delicate balance between thelipophilic and hydrophilic strengths of these groups. Since ester links (as in procaine) aremore prone to hydrolysis than amide links, esters usually have a shorter duration of action.(Miller & Hondeghem, (1995), "Local Anesthetics" inBasic & Clinical Pharmacology, 6^thEdition, Ed. by Katzung).

Local anesthetics are usually administered by injection into the area of the nervefibers to be blocked. Thus, absorption and distribution are not as important in controlling theonset of effect as in determining the rate of offset of anesthesia and the likelihood of centralnervous system and cardiac toxicity. Topical application of local anesthetics, however,requires drug diffusion for both onset and offset of anesthetic effect. Therefore, the solubilityand stability of the drug becomes major factors in determining the therapeutic effects of thedrug. (Miller & Hondeghem, (1995), "Local Anesthetics" inBasic & Clinical Pharmacology,6^th Edition, Ed. by Katzung).

Among the local anesthetics, lidocaine, 2-(diethylamino)-N-(2,6-dimethylphenyl)-acetamide,is particularly known for its treatment of ventricular tachycardia (an arrythmia ofthe heart) as an intravenous injection solution. (Seee.g., U.S. Patent No. 3,968,205). Lidocaine is also widely used as a vasoconstrictor to reduce regional blood flow in topicalapplications or aerosols (such as nasal aerosols to reduce nasal congestion). (Seee.g., U.S.Patent No. 5,534,242). In addition, lidocaine is known for its therapeutic effects in reducingpost-herpetic neuralgia (PHN) nerve injury pain from shingles (herpes zoster and postherpetic neuralgia) and analogous neuropathies. For example, U.S. Patent No. RE37,727discloses methods employing lidocaine intradermal administration by transport lidocainefrom the skin surface, using patches and dressings, into the skin.

Lidocaine base is freely lipid soluble. It is insoluble in water and thus not suitable foruse in an aqueous suspension, requiring ethanol or the like to obtain a liquid solution.However, its salt form, lidocaine-HCl, is very soluble in water and alcohol. Thus, lidocaine-HClis generally the form that is used for preparation of injection solution.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely useddrugs, probably due to their therapeutic properties as anti-inflammatories, analgesics, antipyretics,and anti-thrombolics and are used to treat a variety of clinical conditionsmanifesting such symptoms as pain, inflammation, fever, and to treat and preventatherosclerosis. While these drugs are highly effective, oral administration of many NSAIDscan cause serious adverse effects such as gastrointestinal bleeding and ulceration, liver andkidney damages, and central nervous system and cutaneous disturbances, particularly afterextended use. Therefore, in an effort to minimize the adverse effects associated with oraladministration, non-oral delivery of NSAIDs has been extensively investigated in recentyears.

Transdermal delivery, in particular, is an attractive option because it avoids thehepatic first-pass metabolism, reduces the side effects associated with oral administration, is associated with higher patient compliance and, in some cases, enhances therapeutic efficacyof the drug.

Transdermal delivery of NSAIDs is particularly useful for treatment of rheumatoidarthritis and related conditions, which are characterized by painful and swollen joints due toinflammation in the musculoskeletal tissues of the joints. However, although topicaladministration of certain NSAIDs, such as naproxen, ketoprofen, diclofenac, piroxicam andibuprofen, has been shown to deliver the drug to the local musculoskeletal tissues of jointswhere arthritic conditions often develop, due to the low solubility of NSAIDs in water, theeffectiveness of topical administration of NSAIDs is limited by the inability of these drugs topermeate the skin.

In the conventional topical formulations of NSAIDs that are commercially available,the active ingredients are simply dissolved, dispersed or otherwise formulated in a suitablepharmaceutical vehicle. The thermodynamic activity of the drug in such formulations isrelatively low due to the limited solubility of drugs in the vehicle. In recent years,improvement of the dermal permeation of NSAIDs has been introduced, which includes theincrease of lipophilicity of the drug, the incorporation of the drug into lipid vesicles such asliposomes, and the employment of a permeation enhancer in the formulation. However, theresults of these approaches are largely unsatisfactory.

Recently, U.S. Patent No. 6,368,618 B1 discloses a topical formulation for delivery ofNSAIDs using a two phase liquid composition containing aqueous and oil phases. U.S.6,420,394 discloses yet another topical pharmaceutical formulations for NSAIDs, whichincludes the addition of sodium phosphate buffer and optionally an alcoholic solvent toincrease the permeation of NSAIDs. However, based on the facts that the absence of effective transdermal formulations of NSAIDs in the marketplace, efforts directed towardimproving the delivery system of NSAIDs are desperately needed.

Contrary to local anesthetics, NSAIDs are weak acid. There are roughly nine majorclasses of NSAIDs, which are salicylate derivatives (such as acetosalicylate [aspirin]),propionic acid derivatives (such as ibuprofen), aniline derivatives (such asaminophenolacetaminophen [tylenol]), pyrazole derivatives (such as phenylbutazone), N-arylanthranilicacid (or fenamates) derivatives (such as meclofenamate), indole derivatives(such as indomethacin), acetic acid derivatives (such as diclofenac), oxicam derivatives (suchas piroxicam), and miscellaneous others (such as celecoxib).

Among the NSAIDs, diclofenac, which is 2-(2,6-dichloro-anilino)-phenyl-acetic acid,is particularly known for its role as an anti-rheumatic agent for treatment of rheumatoidarthritis. Diclofenac belongs to the acetic acid class of NSAID. Due to its relatively lowsolubility in water, an aqueous injection solution of diclofenac is difficult to achieve.

U.S. Patent No. 4,711,906 discloses a liquid diclofenac preparation where a betterdissolution of the diclofenac is obtained when a local anesthetic, lidocaine, is added. Thisliquid diclofenac preparation is particularly suitable for use as injection solution.

Another NSAID similar to diclofenac and also belongs to the acetic acid class ofNSAIDs is ketorolac. Ketorolac is comparable to opioids in terms of providing pain relief.For example, the overall analgesic effect of 30 mg of ketorolac is equivalent to that of 6 to 12mg of Morphine.

Ketorolac is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid. It is aderivative of pyrrolizine carboxylic acid and is structurally related to tolmetin and zomepirac.Like diclofenac, the free acid form of ketorolac has very low solubility in water. The most commonly used salt form of ketorolac is ketorolac tromethamine, which is much more watersoluble than the free acid form of ketorolac.

There are various dosage forms/formulations for ketorolac tromethamine. Forexample, U.S. Patent No. 6,090,368 discloses a pharmaceutical composition comprisingketorolac tromethamine admixed with an aqueous bioadhesive cellulosic polymer containingmicrocrystalline particles. The pharmaceutical composition is particularly useful for use innasal spray. U.S. Patent No. 5,414,011 discloses an ophthalmic formulations consisting ofketorolac alone or in combination with an antibiotic drug, and a preservative system having aquaternary ammonium preservative and a nonionic polyoxyethylated octylphenol surfactant.U.S. Patent No. 5,883,115 discloses a transdermal delivery of an eutomer of ketorolac.

Ketorolac is a chiral drug which contains racemic mixture of [-]S form and [+]R form.The biological activity of ketorolac is with the S form. An eutomer is the stereoisomer of achiral drug that exhibits greater pharmaceutical activity than its counterpart stereoisomer. Inthis case, the eutomer is the S form of ketorolac. U.S. Patent No. 6,333,044 discloses atherapeutic composition of the racemic active form of ketorolac (i.e., the S form), incombination with a pharmaceutically acceptable excipient or diluent, for use in intranasaladministration.

In the invention to be presented below, a group of novel pharmaceutically acceptablesalts containing local anesthetic and anti-inflammatory effects is introduced. Thesepharmaceutically acceptable salts can be categorized as a "NSAID salt of a local anesthetic."These salts are further characterized by their unique physical and chemical properties, whichresemble neither NSAIDs nor local anesthetics that they are originated from. Thesepharmaceutically acceptable salts not only have improved therapeutic activities for pain relief, but also demonstrate far much better solubility when used in parenteral injection andtransdermal permeation when used in topical treatments.

SUMMARY OF THE INVENTION

The present invention provides novel pharmaceutically acceptable salts, eachcontaining a local anesthetic and anti-inflammatory activity. The preferred one is adiclofenac salt of lidocaine, which has unique characteristics distinguishable from eitherdiclofenac alone or lidocaine alone, based on the testing results in differential scanningcolorimetry (DSC), thermo-gravimetric analysis (TGA), and Fourier-Transformed InfraredSpectroscopy (FTIR). Diclofenac belongs to the group of non-steroidal anti-inflammatorydrug (NSAID). Lidocaine is a member of a group of local anesthetics.

The diclofenac portion of the salt is freely replaceable with another NSAID, as longas the NSAID is not a salicylic acid derivative; the lidocaine portion of the salt is also freelyreplaceable with another local anesthetic to form another pharmaceutically acceptable salt ofthe present invention.

Examples of the NSAID that can be used to replace diclofenac include, but are notlimited to, etodolac, ketorolac, bromfenac, ibuprofen, fenoprofen, fluriboprofen, ketoprofen,naproxen, suprofen, meclofenamate, mefenamic acid, piroxicam, meloxicam, indomethacin,sulindac, phenylbutazone, oxyphenbutazone, tolmetin, and celecoxib. Among these NSAIDs,ketorolac is the preferred one.

Examples of the local anesthetics that can be used to replace lidocaine include, butare not limited to, butacaine, chloroprocaine, cocaine, cyclomethycaine, hexyclaine, procaine, proparacaine, propoxycaine, tetracaine, benzocaine, bupivacaine, dibucaine, etidocaine,lidocaine, mepivacaine, ropivacaine, prilocaine, dyclonine, and pramoxine.

The present invention also includes a method for making the pharmaceuticallyacceptable salts which include: (1) dissolving a lidocaine and a diclofenac in a solvent toform a drug mixture; and (2) removing the solvent from the drug mixture to form thepharmaceutically acceptable salt. The lidocaine and the diclofenac are either dissolved in thesolvent respectively or mixed together prior to dissolving in the solvent. The lidocaine iseither a free base of lidocaine or lidocaine-HCl. The diclofenac is a free acid of diclofenac,sodium diclofenac, potassium diclofenac, or diethylamine diclofenac.

The lidocaine portion of the salt is freely replaceable with a free base or a salt ofanother local anesthetic. The diclofenac portion of the salt is also freely replaceable a freeacid or a salt of another NSAID as long as the NSAID is not a salicylic acid derivative.

Any solvent that is capable of dissolving NSAID and local anesthetic is suitable foruse in the present invention. The preferred ones include, but are not limited to, methanol,ethanol, isopropyl alcohol, acetone, toluene, chloroform, dimethylformamide,dimethylacetamide, dimethylsulfoxide, methylene chloride and acetonitrile.

Any conventional methods that can be used to remove the solvent can be used forremoving the solvent from the pharmaceutically acceptale salts of the present invention. Thepreferred methods for removing the solvent include, but are not limited to, crystallized bynatural evaporation, vacuum condensation, or drying under nitrogen.

Another method for making the pharmaceutically acceptable salt of the presentinvention includes: (1) mixing a lidocaine and a diclofenac to form a drug mixture; and (2) pulverizing the drug mixture by a physical-mechanical means to form thepharmaceutically acceptable salt of the present invention. An example of the physical-mechanicalmeas is by pulverizing the drug mixture in a motar with a pestle. The lidocainethat can be used in this method includes, but is not limited to, a free base of lidocaine orlidocaine-HCl. The diclofenac that can be used in this method includes, but is not limited to,a free acid of diclofenac, sodium diclofenac, potassium diclofenac, or diethylaminediclofenac. Additionally, the diclofenac salt of lidocaine can be further purified bydissolving the salt in a suitable solvent followed by evaporating the solvent by naturalevaporation, vacuum condensation, or drying under nitrogen.

Furthermore, the lidocaine portion of the salt is freely replaceable with a free base orsalt of another local anesthetic. The diclofenac portion of the salt is also freely replaceablewith a free acid or salt of another NSAID as long as the NSAID is not a salicylic acidderivative.

The present invention also provides a pharmaceutical formulation which comprisesthe diclofenac salt of lidocaine and a pharmaceutically acceptable carrier. Thepharmaceutical formulation is suitable for use in topical treatment, such as in the forms ofsolution, gel, emugel, cream, ointment, lotion, transdermal patch, or eye drop. Thepharmaceutical formulation is also suitable for parenteral injection.

The pharmaceutical formulation of the present invention is particularly suitable foruse in treating patients with localized pain, such as muscle pain, joint pain, pain associatedwith herpes infection, and wound pain, by topically and parenterally treating these patientswith an effective amount of the pharmaceutical formulation.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 shows a thermogram of differential scanning calorimetry (DSC) spectrum offree base of lidocaine. DSC was run at a heating rate of 2°C per min using DSC V4.OBDuPont Model 2000. The onset temperature of the compound was at 66.87°C. Theendothermal maximum of melting was at 67.93°C.

Figure 2 shows a thermogram of differential scanning calorimetry (DSC) spectrum offree acid of diclofenac. DSC was run at a heating rate of 10°C/min. The onset temperatureof the compound was at 178.12°C. The endothermal maximum of melting was at 178.99°C.

Figure 3 shows a thermogram of differential scanning calorimetry (DSC) spectrum ofa diclofenac salt of lidocaine formed by dissolving a free base of lidocaine and a free acid ofdiclofenac respectively in acetone before mixing together, followed by removing the solvent.The DSC was run at a heating rate of 10°C/min. The onset temperature was at 96.0°C. Theendothermal maximum of melting is at 99.71 °C.

Figure 4 shows a thermogram of differential scanning calorimetry (DSC) spectrum ofa diclofenac salt of lidocaine formed by dissolving a free base of lidocaine and a free acid ofdiclofenac in isopropyl alcohol before mixing together, followed by removing the solvent.The DSC was run at a heating rate of 10°C/min. The onset temperature was at 95.02°C. Theendothermal maximum of melting was at 101.82°C.

Figure 5 shows a thermogram of differential scanning calorimetry (DSC) spectrum ofa diclofenac salt of lidocaine formed by dissolving a free base of lidocaine and a free acid ofdiclofenac in alcohol, followed by removal of the solvent. The DSC was measured by using aheating rate of 10°C/min. The onset temperature was at 93.16°C. The endothermalmaximum of melting was at 101.49°C.

Figure 6 shows the profile of weight loss versus temperature curve in thermogravimetricanalysis (TGA) spectrum of a free base of lidocaine base. The TGA was run at aheating rate of 10°C/min using 2950 TGA V5.4A Universal V3.4C TA Instrument. Shownin the curve is the % of weight remained of free base lidocaine at 100°C, 200°C, 250°C, and300°C. At 250°C, the % of weight remained was less than 0.1%.

Figure 7 shows the profile of weight loss versus temperature curve inthermogravimetric analysis (TGA) spectrum of a free acid of diclofenac acid. The TGA wasrun at a heating rate of 10°C/min. Shown in the curve is the % of weight remained of freebase lidocaine at 100°C, 200°C, 250°C, and 300°C. At 250°C, the % of weight remainedwas about 35.33%.

Figure 8 shows the profile of weight loss versus temperture curve in thermogravimetricanalysis (TGA) spectrum of a diclofenac form of lidocaine formed by dissolvinga free base of lidocaine and a free acid of diclofenac respectively, in acetone before mixingtogether, followed by removal of the solvent using natural evaporation. The TGA was run ata heating rate of 0°C/min. Shown in the curve is the % of weight remained of the free baseof lidocaine and the free acid of diclofenac at 100°C, 200°C, 250°C, and 300°C. At 250°C,the % of weight remained was about 53.05%.

Figure 9 shows the profile of weight loss versus temperature curve in thermogravimetricanalysis (TGA) spectrum of a diclofenac salt of lidocaine formed by dissolving afree base of lidocaine and a free acid of diclofenac, respectively, in actone before mixingtogether, followed by removal of the solvent using reduced-pressure condensation. The TGAwas run at a heating rate of 10°C/min. Shown in the curve is the % of weight remained of the free base of lidocaine and the free acid of diclofenac at 100°C, 200°C, 250°C, and 300°C.At 250°C, the % of weight remained was about 37.40%.

Figure 10 shows the infra-red (IR) spectrum of diclofenac acid using Fourier-TransformedInfrared Spectroscopy (FTIR). The numbers shown on the graph depicted thepeak wavelengths (cm^-1) which were unique to diclofenac free acid.

Figure 11 shows the IR spectrum of lidocaine using FTIR. The numbers shown on thegraph depicted the peak wavelengths (cm^-1) which were unique to lidocaine free base.

Figure 12 shows the IR spectrum of a mixture containing equal moles of lidocaineand diclofenac acid. The mixture was neither dissolved in solvent nor pulverized. Thenumbers shown on the graph depicted the peak wavelengths (cm^-1) which represented themixture of lidocaine and diclofenac.

Figure 13 shows the IR spectrum of the diclofenac salt of lidocaine which wasprepared by mixing equal moles of lidocaine free base and diclofenac free acid, followed bydissolving the mixture in a solvent and then removing the solvent by vacuum condensation.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel pharmaceutically acceptable salts which exhibitcombined therapeutic effects of local anesthetic and anti-inflammatory activities. Thesepharmaceutical acceptable salts are an ''NSAID salt of a local anesthetic agent." They arecharacterized by their distinctive physical and chemical properties, which are different fromeither the NSAID alone or the local anesthetic agent alone, as demonstrated by the DSC,TGA, HPLC, and FTIR analyses as shown in Figures 1-13.

The ''NSAID salt of the local anesthetic agent" are formed by (1) the interaction ofthe weak acid (NSAID) with the weak base (local anesthetic); and (2) the solvent dissolution-removalor pulverization method employed in the present invention which further enhancesthe salt forming process. The ''NSAID salt of the local anesthetic agent" is readily filteredand easily dried, and, if necessary, can be easily re-purified by re-dissolving the salt in asuitable solvent followed by drying to remove the solvent.

The pharmaceutically acceptable salts of the present invention are prepared inaccordance with the following methods:

Method 1: A chosen NSAID, in its free acid form, is dissolved in a suitable solvent.A chosen local anesthetic agent, in its free base form, is dissolved in the same solvent. Thedissolved NSAID and local anesthetic agent are mixed to form a mixed solution. The solventis removed to produce the pharmaceutically acceptable salt of the present invention.Optionally, the pharmaceutically acceptable salt can be further purified by re-dissolving thesalt in a solvent followed by drying to remove the solvent.

Method 2: A chosen NSAID and a chosen local anesthetic agent, each in itsrespective free acid or free base form, are uniformly mixed and dissolved in a suitablesolvent. The solvent is then removed to produce the pharmaceutically acceptable salt of thepresent invention. Optionally, the pharmaceutically acceptable salt can be further purified byre-dissolving the salt in a solvent followed by drying to remove the solvent.

Method 3: A chosen NSAID and a chosen local anesthetic agent, each in itsrespective free acid or free base form, are uniformly mixed and pulverize using a physical-mechanicalmeans to produce the pharmaceutically acceptable salt of the present invention.Optionally, the pharmaceutically acceptable salt can be re-purified by re-dissolving the salt in a suitable solvent followed by removing the solvent by vacuum evaporation or undernitrogen.

Method 4: A chosen NSAID and a chosen local anesthetic, each in its respective saltform, are either respectively dissolved in a suitable solvent and then mixed together asindicated inMethod 1, or uniformly mixed and then dissolved in a suitable solvent asindicated inMethod 2. Optionally, the dissolved mixture is heated to an elevatedtemperature (which is determined based on the solvent used in dissolving the compounds)followed by cooling to facilitate the formation of the salt. Optionally, the salt can be furtherpurified by re-dissolving the salt in a solvent followed by drying to remove the solvent.

Method 5: A chosen NSAID and a chosen local anesthetic agent, each in itsrespective salt form, are mixed and then pulverized using physical-mechanical means toproduce the pharmaceutically acceptable salt of the present invention. Optionally, the saltcan be further purified by re-dissolving the salt in a solvent followed by drying to remove thesolvent.

The pharmaceutically acceptable salts of the present invention have been confirmedby the following instrumental analyses to be distinctively different from the local anestheticagent and/or the NSAID they originated:

Thermal Analysis: Two thermal analysis, thermogravimetric analysis (TGA) anddifferential scanning calorimetry (DSC) were employed. TGA measures the change in themass of sample as the temperature is changed. The profile of the overall thermogravimetricweight loss versus temperature curve provides reliable indication of the phase and weightchanges of the pharmaceutical compounds.

DSC examines the changes in physical properties of the pharmaceutical compoundwith temperature or time. During operation, DSC heats the test sample, measures heat flowbetween the test sample and its surrounding environment, and records a test thermogram ofthe test sample based on the measured heat flow. DSC provides information regarding theonset temperature, the endothermal maximum of melting, and the enthalpy of thepharmaceutical compound.

High Performance Liquid Chromatography (HPLC): Pharmaceutical compounds canbe characterized and/or purified by HPLC. Alternatively, the content and/or purity of thepharmaceutical compounds can be determined by HPLC method. For a given columnpacking, solvent system, and flow rate, most compounds tend to elute to a certain degreefrom an analytical and/or preparative HPLC column.

UV Spectroscopy: The UV spectroscopy can be used to perform qualitative analysisof the pharmaceutical compounds.

Infrared (IR) Spectroscopy including Fourier-Transformed Infrared Spectroscopy(FTIR): Functional groups of a pharmaceutical compound can be determined by IR spectrabased on their respective light transmittance. The IR spectrum of a pharmaceuticalcompound is presented in a drawing in which the ordinate is the transmittance in % and theabscissa is the wavelength in cm^-1. The IR is extremely sensitive to the structure,conformation, and environment of an organic compound and thus is a suitable method for thecharacterization and identification of different solid forms of drugs. An FTIR microscopeallows the measurement of the IR spectrum of a single crystal or group of crystals. Themicroscope technique minimizes the possibility of obtaining IR spectra of mixture of crystalforms and is a distinct advantage over approaches that use powdered samples.

Liquid Chromatography-Mass Spectroscopy (LC-MS): The molecular weight and thechemical structure of the pharmaceutical compound can be determined using the liquidchromatography-mass spectroscopy (LC-MS) method.

Transdermal Absorption Test: The transdermal absorption of the pharmaceuticalcompound can be determined using the transdermal diffusion measurement instrument.

Local anesthetic agents are basic compounds. They are capable of formingpharmaceutically acceptable acid addition salts of the compounds with strong or moderatelystrong, non-toxic, organic or inorganic acids by methods known to the art. Exemplary of theacid addition salts that are included in this invention are maleate, fumarate, lactate, oxalate,methanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydrochloride,hydrobromide, sulfate, phosphate and nitrate salts. In the examples and experimental resultsto be presented in the following section (infra), an NSAID is proven to be an acid additionsalt of the local anesthetic agents.

NSAIDs are acidic compounds. They can form pharmaceutically acceptable baseaddition salts of the compounds with organic and inorganic bases by conventional methods.Examples of the nontoxic alkali metal and alkaline earth bases include, but are not limited to,calcium, sodium, potassium and ammonium hydroxide; and nontoxic organic bases include,but are not limted to, triethylamine, butylamine, piperazine, and tri(hydroxymethyl)-methylamine.In the examples and experimental results to be presented in the followingsections, a local anesthetic is proven to be a base addition salt of the NSAIDs.

Local anesthetics that are utilized to prepare the pharmaceutical compounds of thepresent invention include, but are not limited to the following classes of compounds: esters (e.g., butacaine, chloroprocaine, cocaine, cyclomethycaine, hexylcaine, procaine,proparacaine, propoxycaine, tetracaine, benzocaine), amide (e.g., bupivacaine, dibucaine,etidocaine, lidocaine, mepivacaine, ropivacaine, prilocaine), dyclonine, pramoxine and thepharmaceutically acceptable salts of the above compounds.

The NSAIDs that are suitable for preparation of the pharmaceutical compounds of thepresent invention include, but are not limited to: acetic acid derivatives (e.g., diclofenac,etodolac, ketorolac, bromfenac, propionic acid derivatives (e.g., ibuprofen, fenoprofen,fluriboprofen, ketoprofen, naproxen, suprofen), fenamates (e.g., meclofenamate, mefenamicacid), oxicam (e.g., piroxicam, meloxicam), indole derivatives (e.g., indomethacin, sulindac),pyrazolone derivatives (e.g., phenylbutazone, oxyphenbutazone), tolmetin, celecoxib, and thepharmaceutically acceptable salts of the above compounds. The preferred NSAIDs arediclofenac and ketorolac.

In addition, when comparing to the individual NSAIDs and local anesthetics, thepharmaceutically acceptable salts of the present invention, which are prepared by mixingequal moles of NSAIDs and local anesthetics together followed by crystallization, possessimproved aqueous solubility as well as enhanced transdermal absorption of the skin. Theseimprovements enable the preparations of the pharmaceutically acceptable salts in manydifferent formulations with ease which in turn offer more treatment options to the patients.These improvements simplify the manufacturing process and maintain the product quality ofthe pharmaceutically acceptable salts of the present invention.

The pharmaceutical acceptable salts of the present invention are particularly suitablefor formulations as injection solution and/or topical preparations. In the injection solution,the pharmaceutically acceptable salts are preferably first dissolved in benzyl alcohol. The dissolved pharmaceutical acceptable salts are then mixed with methyl paraben and propylparaben, before the addition of water.

Formulations suitable for topical administration include liquid or semi-liquidpreparations suitable for penetration through the skin to the site of where treatment isrequired. Examples of liquid preparations include, but are not limited to topical solution ordrops (such as eye, ear, or nose drops). Examples of semi-liquid preparations include, butare not limited to liniments, lotions, creams, ointment or paste, gel, emugel. Thepharmaceutical ingredients are in general those commonly used and generally recognized byperson skilled in the art of pharmaceutical formulation.

Topical solution or eye drops of the present invention may contain aqueous or oilysolution or suspensions. They may be prepared by dissolving the pharmaceutical compoundin a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any othersuitable preservative, and preferably including a surface active agent. For eye drops, it ispreferred that the resulting solution be clarified by filtration, transferred to a suitablecontainer which is then sealed and sterilized by autoclaving. As for other topicalpreparations, sterilization is generally not required.

Examples of bactericidal and fungicidal agents suitable for inclusion in the dropsinclude, but are not limited to, phenylmercuric nitrate or acetate (0.002%), benzalkoniumchloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation ofan oily solution include glycerol, diluted alcohol and propylene glycol. Optionally, L-mentholcan be added to the topical solution.

Lotions and liniments according to the present invention include those suitable forapplication to the skin, which contain a sterile aqueous solution and optionally a bactericide. They may also include an agent to hasten drying and cooling of the skin, such as alcohol oracetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

Cream, ointments or pastes are semi-solid formulations. They may be made bymixing the pharmaceutically acceptable salts in finely-divided or powdered form, alone or insolution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may contain hydrocarbons. Examples of thehydrocarbons include, but are not limited to, hard, soft, or liquid paraffin, glycerol, beeswax,a metallic soap, a mucilage, an oil of natural origin (such as almond, corn, arachis, castor orolive oil), wool fat or its derivative, and/or a fatty acid (such as stearic acid or oleic acid).The formulation may also contain a surface active agent, such as anionic, cationic or nonionicsurfactant. Examples of the surfactants include, but are not limited to, sorbitan esters orpolyoxyethylene derivatives thereof (such as polyoxyethylene fatty acid esters), andcarboxypolymethylene derivatives thereof (such as carbopol). Suspending agents such asnatural gums, cellulose derivatives inorganic materials such as silicaceous silicas, and otheringredients such as lanolin, may also be included. For ointment, polyethylene glycol 540,polyethylene glycol 3350, and propyl glycol may also be used to mixed with thepharmaceutical compound.

A gel or emugel formulation of the present invention includes any gel forming agentcommonly used in pharmaceutical gel formulations. Examples of gel forming agents arecellulose derivtives such as methyl cellulose, hydroxyethyl cellulose, and carboxymethylcellulose; vinyl polymers such as polyvinyl alcohols, polyvinyl pyrrolidones; andcarboxypoly-methylene derivatives such as carbopol. Further gelling agents that can be usedfor the present invention are pectins, gums (such as gum arabic and tragacanth, alginates, carrageenates, agar and gelatin). The preferred gelling agent is carbopol. Furthermore, thegel or emugel formulation may contain auxiliary agents commonly used in this kind offormulations such as preservatives, antioxidants, stabilizers, colorants and perfumes.

The following examples are illustrative, but not limiting the scope of the presentinvention. Reasonable variations, such as those occur to reasonable artisan, can be madeherein without departing from the scope of the present invention.

EXAMPLE 1Preparation of A Diclofenac Salt of Lidocaine By Lidocaine Free Baseand Diclofenac Free Acid

The diclofenac salt of lidocaine in Example 1 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Lidocaine Free Base	23.434 g
Diclofenac Free Acid	29.615g
Alcohol
	120 mL

Method 1:

Lidocaine free base (23.434 g) was dissolved in 20 mL of alcohol. Diclofenac Freeacid (29.615 g) was dissolved in 100 mL of alcohol. The dissolved lidocaine free base anddiclofenac free acid solutions were thoroughly mixed. The diclofenac salt of lidocaine ofExample 1 was obtained by removing the alchohol by natural evaporation (i.e., by allowingthe sample to be naturally evaporated), reduced-pressure or vacuum condensation, or dryingunder nitrogen until complete dryness.

Method 2:

Lidocaine free base (23.434 g) and diclofenac free acid (29.615 g) were thoroughlymixed and then added to 120 mL of alcohol. Alternatively, lidocaine free base anddiclofenac free acid were sequentially added to alcohol. The resultant mixture was thenstirred until the mixture were dissolved. The diclofenac salt of lidocaine of Example 1 wasobtained as removing the alcohol by natural evaporation, reduced-pressure or vacuumcondensation, or drying under nitrogen until the sample was completely dried.

EXAMPLE 2Preparation of A Diclofenac Salt of Lidocaine By Lidocaine Free Baseand Diclofenac Free Acid

The diclofenac salt of lidocaine of Example 2 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Lidocaine Free Base	2.3434 g
Diclofenac Free Acid	2.9615g
Alcohol
	120 mL

Method 1:

Lidocaine free base (2.3434 g) was dissolved in 20 mL of alcohol. Diclofenac freeacid (2.9615 g) was dissolved in 100 mL alcohol with optional heating to facilitatedissolution. The dissolved solutions of lidocaine free base and diclofenac free acid weremixed. The diclofenac salt of lidocaine of Example 2 was obtained by removing the alcoholby natural evaporation, reduced-pressure or vacuum condensation, or drying under nitrogenuntil the sample was completely dried.

Method 2:

Lidocaine free base (2.3434 g) and diclofenac free acid (2.9615 g) were thoroughlymixed and then added to 120 mL alcohol. Alternatively, lidocaine free base and diclofenacfree acid were sequentially added to alcohol. The resultant mixture was then stirred until themixture was dissolved. The diclofenac salt of lidocaine of Example 2 was obtained byremoving the alcohol by natural evaporation, reduced-pressure or vacuum condensation, ordrying under nitrogen until the sample was completely dried.

EXAMPLE 3Preparation of A Diclofenac Salt of Lidocaine By Lidocaine Free Baseand Diclofenac Free Acid

The diclofenac salt of lidocaine of Example 3 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Lidocaine Free Base	23.434 g
Diclofenac Free Acid	29.615g
Isopropyl Alcohol
	120 mL

Method 1:

Lidocaine base (23.434 g) was dissolved in 20 mL of isopropyl alcohol. Diclofenacacid (29.615 g) was dissolved in 100 mL of isopropyl alcohol with optional heating tofacilitate the dissolution. The dissolved solutions of lidocaine and diclofenac were mixed.The diclofenac salt of lidocaine of Example 3 was obtained by removing the isopropylalcohol by nature evaporation, reduced-pressure or vacuum condensation, or drying undernitrogen until the sample was completely dried.

Method 2:

Lidocaine free base (23.434 g) and diclofenac free acid (29.615 g) were mixed andthen added to 120 mL of isopropyl alcohol. Alternatively, lidocaine free base and diclofenacfree acid were seqentially added to isopropyl alcohol. The resultant mixture was then stirreduntil the mixture was completely dissolved. The diclofenac salt of lidocaine of Example 3was obtained by removing the isopropyl by natural evaporation, reduced-pressure or vacuumcondensation, or drying under nitrogen until the sample was completely dried.

EXAMPLE 4Preparation of A Diclofenac Salt of Lidocaine By Lidocaine Free Baseand Diclofenac Free Acid

The diclofenac salt of lidocaine of Example 4 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Lidocaine Free Base	23.434 g
Diclofenac Free Acid	29.615 g
Acetone	210 mL

Method 1:

Lidocaine free base (23.434 g) was dissolved in 10 mL acetone. Diclofenac free acid(29.615 g) was dissolved in 210 mL of acetone with optional heating to facilitate thedissolution. The dissolved solutions of lidocaine free base and diclofenac free acid werethoroughly mixed. The diclofenac salt of lidocaine of Example 4 was obtained by removingthe acetone by natural evaporation, reduced-pressure or vacuum condensation, or dryingunder nitrogen until the sample was completely dried.

Method 2:

Lidocaine free base (23.434 g) and diclofenac free acid (29.615 g) were mixed andthen added to 210 mL of acetone. Alternatively, lidocaine free base and diclofenac free acidwere sequentially added to acetone. The resultant mixture was then stirred until the mixturewas completely dissolved. The diclofenac salt of lidocaine of Example 4 was obtained byremoving the acetone by natural evaporation, reduced-pressure or vacuum condensation, ordrying under nitrogen, until the sample was completely dried.

EXAMPLE 5Preparation of A Diclofenac Salt of Lidocaine By Lidocaine Free Baseand Diclofenac Free Acid

The diclofenac salt of lidocaine of Example 5 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Lidocaine Free Base	23.434 g
Diclofenac Free Acid	29.615g
Toluene
	500 mL

Method 1:

Lidocaine free base (23.434 g) was dissolved in 500 mL toluene. Diclofenac freeacid (29.615 g) was added to the toluene solution containing dissolved lidocaine free base.The mixture was stirred until complete dissolution. The diclofenac salt of lidocaine ofExample 5 was obtained by removing the toluene by natural evaporation, reduced-pressure orvacuum condensation, or drying under nitrogen, until the sample was completely dried.

Method 2:

Lidocaine free base (23.434 g) and diclofenac free acid (29.615 g) were mixed andthen added to 500 mL of toluene. Alternatively, lidocaine free base and diclofenac free acidwere mixed or sequentially added to toluene. The resultant mixture was then stirred until themixture was dissolved. The diclofenac salt of lidocaine of Example 5 was obtained byremoving the toluene by natural evaporation, reduced-pressure or vacuum condensation, ordrying under nitrogen, until the sample was completely dried.

EXAMPLE 6Preparation of A Diclofenac Salt of Lidocaine By Lidocaine-HCl and Diclofenac-Diethylamine

The diclofenac salt of lidocaine of Example 6 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Lidocaine-HCl	25 g
Diclofenac Diethylamine	5.8g
Isopropyl Alcohol
	100 mL

Method 1:

Lidocaine-HCl (25 g) was dissolved in isopropyl alcohol. Diclofenac aciddiethylamine (5.8 g) was dissolved in isopropyl alcohol. The diclofenac solution was addedto the lidocaine solution and mixed to form a uniform solution. The diclofenac salt oflidocaine of Example 6 was obtained by removing the isopropyl by natural evaporation,reduced-pressure or vacuum condensation, or drying under nitrogen, until the sample wascompletely dried.

Method 2:

Lidocaine-HCl hydrochloride (25 g) and diclofenac diethylamine (5.8 g) were mixedand then added to 100 mL of isopropyl alcohol. The resultant mixture was then stirred untilthe mixture was completely dissolved. The diclofenac salt of lidocaine of Example 6 wasobtained by removing the isopropyl by natural evaporation, reduced-pressure or vacuumcondensation, or drying under nitrogen, until the sample was completely dried.

EXAMPLE 7Preparation of A Topical Solution Containing A Diclofenac Salt of Lidocaine Made ByLidocaine Free Base and Diclofenac Free Acid

The topical solution of Example 7 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Diclofenac Free Acid	29.615 g
Lidocaine Free Base	23.434 g
L-Menthol	2 g
Acetone	210 mL
Alcohol	5280 mL
Purified water	2640 mL
TOTAL WEIGHT	8000 mL

Method:

(1) Lidocaine free base (23.434 g) was dissolved in acetone (10 mL) with stirring.

(2) Diclofenac free acid (29.615 ml) was dissolved inacetone 200 mL withstirring.

(3) The solutions of (1) and (2) were mixed to form a uniform solution. Theresultant solution was condensed under reduced pressure to produce a pharmaceuticalcompound of the present invention.

(4) The pharmaceutical compound of (3) was dissolved in alcohol 4000 g.

(5) L-menthol (2 g) was added to the solution of (4) and mixed until completedissolution. Purified water (2640 mL) was added to the resultant solution to a final volumeof 8000 mL to produce the topical solution of the present invention.

EXAMPLE 8Preparation of An Injection Solution Containing A Diclofenac Salt of Lidocaine Made ByLidocaine Free Base and Diclofenac Free Acid

The injection solution of Example 8 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Diclofenac Free Acid	29.615 g
Lidocaine Free Base	23.434 g
Acetone	210mL
Benzyl Alcohol
	500 mL
Methyl Paraben	1.8 mg
Propyl Paraben	0.2 mg
Water For Injection	q.s. to 10000 mL

Method:

(1) Lidocaine free base (29.615 g) was dissolved in acetone (10 mL) with stirring.

(2) Diclofenac free acid was dissolved in acetone (200 mL) with stirring.

(3) The solutions of (1) and (2) were mixed to form a uniform solution. Theresultant solution was condensed under reduced pressure or vacuum condition to obtain apharmaceutical compound of the present invention.

(4) The pharmaceutical compound of (3) was dissolved in benzyl alcohol (500mL) with stirring. Optionally, mild heating was applied to facilitate the dissolution.

(5) Methyl paraben (1.8 mg) and propyl paraben (0.2 mg) were added to thesolution of (4) and mixed until complete dissolution. The resultant solution was q.s. withwater to a final volume of 10000 mL. The solution was then passed through a 0.22µm filterto form the injection solution of the present invention.

EXAMPLE 9Preparation of A Cream Containing A Diclofenac Salt of Lidocaine Made By Lidocaine FreeBase and Diclofenac Free Acid

The cream of Example 9 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Diclofenac Free Acid	29.615 g
Lidocaine Free Base	23.434 g
Acetone	210 mL
Polyoxyethylene fatty acid esters	200 g
Carboxypolymethylene (Carbopol)	50 g
Purified Water	100 g
TOTAL WEIGHT	1000 g

Method:

(1) Lidocaine free base (29.615 g) was dissolved in acetone (10 mL) with stirring.

(2) Diclofenac free acid was dissolved in acetone (200 mL) with stirring.

(3) The solutions of (1) and (2) were mixed to form a uniform solution. Theresultant solution was condensed under reduced pressure or vacuum condition to obtain adiclofenac salt of lidocaine of the present invention.

(4) The compound of (3) and polyoxyethylene fatty acid esters (200 g) weremixed and stirred with heating to form a uniform liquid.

(5) Carboxypolymethylene (50 g) and purified water (500 g) were mixed to forma uniform liquid.

(6) The liquids of (4) and (5) were mixed to form a uniform mixture. Purifiedwater 196.951 g was added to the resultant mixture and stirred until a uniform mixture wasformed to form the cream of the present invention.

EXAMPLE 10Preparation of An ointment Containing A Diclofenac Salt of Lidocaine Made By LidocaineFree Base and Diclofenac Free Acid

The ointment of Example 10 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Diclofenac Free Acid	29.615 g
Lidocaine Free Base	23.434 g
Acetone	210 mL
Polyethylene glycol 540	200 g
Polyethylene Glycol 3350	646.951 g
Propyl glycol	100 g
TOTAL WEIGHT	1000 g

Method:

(1) Lidocaine free base (29.615 g) was dissolved in acetone (10 mL) with stirring.

(2) Diclofenac free acid was dissolved in acetone (200 mL) with stirring.

(3) The solutions of (1) and (2) were mixed to form a uniform solution. Theresultant solution was condensed under reduced pressure or vacuum condition to obtain adiclofenac salt of lidocaine of the present invention.

(4) The compound of (3), polyethylene glycol 540 (200 g), and polyethyleneglycol 3350 were mixed and stirred with heat to form a uniform liquid.

(5) The mixture of (4) and propyl glycol were mixed and stirred until a uniformmixture was formed to produce the pharmaceutical ointment of the present invention.

EXAMPLE 11Preparation of A Diclofenac Salt of Lidocaine Containing Lidocaine-HCl and Diclofenac-Sodium

The pharmaceutical compound in Example 11 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Lidocaine HCl	28.884 g
Diclofenac Sodium	31.813 g
Alcohol	320 mL

Method 1:

Lidocaine-HCl (28.884 g) was dissolved in 200 mL of alcohol. Diclofenac sodium(31.813 g) was dissolved in 120 mL of alcohol. The dissolved lidocaine-HCl and diclofenacsodium solutions were thoroughly mixed. The diclofenac salt of lidocaine of Example 11was obtained by removing the alcohol by natural evaporation, vacuum condensation, ordrying under nitrogen, until the sample was completely dried.

Method 2:

Lidocaine-HCl (28.884 g) and diclofenac sodium (31.813 g) were thoroughly mixedand then added to 320 mL of alcohol. Alternatively, lidocaine-HCl and diclofenac sodiumwere sequentially added to alcohol. The resultant mixture was then stirred until the mixturewere dissolved. The diclofenac salt of lidocaine of Example 11 was obtained by removingthe alcohol by natural evaporation, reduced-pressure or vacuum condensation, or dryingunder nitrogen, until the sample was completely dried.

EXAMPLE 12Preparation of A Diclofenac Salt of Lidocaine By Lidocaine-HCl and Diclofenac-Sodium

The diclofenac salt of lidocaine of Example 12 contained the following ingredients:

Ingredients	Weight (g) or Volume (ml)
Lidocaine-HCl	28.884 g
Diclofenac Sodium	31.813 g
Isopropyl Alcohol	320 mL

Method 1:

Lidocaine-HCl (28.884 g) was dissolved in 120 mL of isopropyl alcohol. Diclofenacsodium (31.813 g) was dissolved in 200 mL of isopropyl alcohol. The solutions of lidocaine-HCland diclofenac sodium were mixed. The diclofenac salt of lidocaine of Example 12 wasobtained by removing the isopropyl by natural evaporation, reduced-pressure or vacuumcondensation, or drying under nitrogen, until the sample was completely dried.

Method 2:

Lidocaine-HCl (28.884 g) and diclofenac sodium (31.813 g) were mixed and thenadded to 320 mL of isopropyl alcohol. Alternatively, diclofenac sodium and lidocainehydrochloride were sequentially added to isopropyl alcohol. The resultant mixture was thenstirred until the mixture was completely dissolved. The diclofenac salt of lidocaine ofExample 12 was obtained by removing the isopropyl alcohol by natural evaporation,reduced-pressure or vacuum condensation, or drying under nitrogen until the sample wascompletely dried.

EXAMPLE 13Preparation of A Ketorolac Salt of Lidocaine By Lidocaine Free Baseand Ketorolac Free Acid

The ketorolac salt of lidocaine pharmaceutical compound of Example 13 containedthe following ingredients:

Ingredients	Weight (g)
Ketorolac Free Acid	25.5 g
Lidocaine Free Base	23.434 g
Isopropyl Alcohol	500 g

Method 1:

Ketorolac free acid (25.5 g) was dissolved in isopropyl alcohol (300 mL) with stirring.Lidocaine free base (23.434 g) was dissolved with stirring in 200 mL isopropyl alcohol. Thesolutions of ketorolac and lidocaine were mixed to form a uniform solution. The ketorolacsalt of lidocaine of the present invention was obtained by removing the isopropyl alcohol bynatural evaporation, reduced-pressure or vacuum condensation, or drying under nitrogen untilthe sample was completely dried.

Method 2:

Ketorolac free acid and lidocaine free base were mixed and then added to isopropylalcohol. Alternatively, ketorolac free acid and lidocaine free base were sequentially added toisopropyl alcohol. The resultant mixture was then stirred until the solids were dissolved.The ketorolac salt of lidocaine of the present invention was obtained by removing theisopropyl alcohol by natural evaporation, reduced-pressure or vacuum condensation, ordrying under nitrogen, until the sample was completely dried.

EXAMPLE 14Preparation of A Ketorolac Salt of Lidocaine By Lidocaine Free Baseand Ketorolac Free Acid

The ketorolac salt of lidocaine of Example 14 contained the following ingredients:

Ingredients	Weight (g)
Ketorolac Free Acid	25.5 g
Lidocaine Free Base	23.434 g
Alcohol	500 g

Method 1:

Ketorolac free acid (25.5 g) was dissolved in alcohol (300 mL) with stirring.Lidocaine free base (23.434 g) was dissolved with stirring in 200 mLof alcohol. Thesolutions of ketorolac and lidocaine were mixed to form a uniform solution. The ketorolacsalt of lidocaine of the present invention was obtained by removing the alcohol by naturalevaporation, reduced-pressure or vacuum condensation, or drying under nitrogen until thesample was completely dried.

Method 2:

Ketorolac free acid and lidocaine free base were mixed and then added to alcohol.Alternatively, ketorolac free acid and lidocaine free base were sequentially added to alcohol.The resultant mixture was then stirred until the solids were dissolved. The ketorolac salt oflidocaine of the present invention was obtained by removing the alcohol by naturalevaporation, reduced-pressure or vacuum condensation, or drying under nitrogen, until thesample was completely dried.

EXAMPLE 15Preparation of An Injection Solution Containing A Ketorolac Salt of Lidocaine Made ByLidocaine Free Base and Ketorolac Free Acid

The pharmaceutical compound of Example 15 contained the following ingredients

Ingredients	Weight (g) or Volume (ml)
Ketorolac Free Acid	25.5 g
Lidocaine Free Base	23.434 g
Alcohol	500 g
Water For Injection	q.s. to 1000 mL
sodium chloride	9 mg

Method:

(1) Ketorolac free acid (25.5 g) was dissolved in alcohol (300 mL) with stirring.

(2) Lidocaine free base (23.434 g) was dissolved in alcohol (200 mL) withstirring.

(3) The solutions of ketorolac free acid and lidocaine free base were mixed toform a uniform solution. The solution was sterile-filtered and then condense under reducedpressure or vacuum condition to produce a pharmaceutical compound of the presentinvention.

(4) The compound of (3) was dissolved, with stirring, in 400 mL of purified water.Sodium chloride was added to the resultant solution and stirred until the sample wascompletely dissolved.

(5) Additional water was added to the solution of (4) to q.s. the a final volume to1000 mL. The resultant aqueous solution was passed through a 0.22 µm filter to provide thesterile pharmaceutical injection solution of Example 15.

EXAMPLE 16Preparation of A Ketorolac Salt of Lidocaine By Lidocaine Free Baseand Ketorolac Free Acid

The pharmaceutical compound of Example 16 contained the following ingredients:

Ingredients	Weight (g)
Ketorolac Free Acid	25.5 g
Lidocaine Free Base	23.434 g

Method:

Ketorolac free acid and lidocaine free base were mixed and then pulverized in amortar with a pestle or using other physical mechanical forces to produce the ketorolac saltof lidocaine. The ketorolac salt of lidocaine could be further purified by dissolving the salt ina solvent followed by removing the solvent by evaporation, reduced-pressure or vacuumcondensation, or drying under nitrogen.

EXAMPLE 17Preparation of A Ketorolac Salt of Lidocaine By Lidocaine Hydrochloride and KetorolacTromethamine

The diclofenac salt of lidocaine of Example 17 contained the following ingredients:

Ingredients	Weight (g)
Ketorolac Tromethamine	25 g
Lidocaine Hydrochloride	28.884 g

Method:

Ketorolac tromethamine (25 g) and lidocaine hydrochloride (28.884 g) were mixedand then pulverized in a mortar with a pestle or using other physical mechanical forces to produce the ketorolac salt of lidocaine. The ketorolac salt of lidocaine could be furtherpurified by dissolving the sample in a solvent followed by removing the solvent byevaporation, reduced-pressure or vacuum condensation, or drying under nitrogen.

EXAMPLE 18Preparation of A Diclofenac Salt of Lidocaine By Lidocaine Hydrochlorideand Diclofenac Sodium

The pharmaceutical compound of Example 18 contained the following ingredients:

Ingredients	Weight (g)
Lidocaine Hydrochloride	28.884 g
Diclofenac Sodium	31.813 g

Method:

Lidocaine hydrochloride (28.884 g) and diclofenac sodium (31.813 g) were mixedand then pulverized in a mortar with a pestle or using other physical mechanical forces toproduce the diclofenac salt of lidocaine. The diclofenac salt of lidocaine could be furtherpurified by dissolving the compound in a solvent followed by removing the solvent byevaporation, reduced-pressure or vacuum condensation, or drying under nitrogen.

EXAMPLE 19Preparation of A Diclofenac Salt of Lidocaine By Lidocaine Free Baseand Diclofenac Free Acid

The diclofenac salt of lidocaine of Example 19 contained the following ingredients:

Ingredients	Weight (g)
Lidocaine Free Base	23.434 g
Diclofenac Free Acid	29.615 g

Method:

Lidocaine free base (23.434 g) and diclofenac (29.615 g) were mixed and thenpulverized in a mortar with a pestle or using other physical mechanical forces to produce thediclofenac salt of lidocaine. The diclofenac salt of lidocaine could be further purified bydissolving the sample in a solvent followed by removing the solvent by evaporation, reduced-pressureor vacuum condensation, or drying under nitrogen.

The characteristics of the above Examples were further determined using thefollowing instruments: (1) HPLC, (2) UV Spectroscopy, (3) FTIR, (4) LC-MS, (5) DSC, and(6) TGA. The results demonstrate that the pharmaceutically acceptable salts werecompounds that were physically and chemically different from the NSAID alone or the localanesthetic agent alone, as shown by DSC thermogram, TGA weight loss profile, IR spectrumand HPLC.

The following Experimental Examples 1-4 are selective results of thepharmaceutically acceptable salts analyzed by HPLC (Experimental Example 1), DSC(Experimental Example 2), and TGA (Experimental Example 3) and FTIR (ExperimentalExample 4). These Experimental Examples are for illustrative purpose. They are notintended to limit the scope of the present invention. Reasonable variations, such as those occur to reasonable artisan, can be made herein without departing from the scope of thepresent invention.

EXPERIMENTAL EXAMPLE 1HPLC analysis of A Diclofenac Salt of Lidocaine Made By Lidocaine Free BaseAnd diclofenac Free Acid

HPLC analysis was conducted using a mobile phase of CH₃CN : 10% HOAc = 40 :60 (v/v). The flow rate was at 2.0 ml per min. The compound was detected at a wavelengthof 230 nm.

The pharmaceutically acceptable salt of Experimental Example 1 was preparedaccording to Example 1 (supra) by mixing equal moles of lidocaine free base and diclofenacfree acid in alcohol followed by removing the alcohol by evaporation. If the resultingdiclofenac salt of lidocaine was a simple mixture of lidocaine and diclofenac, the weightpercents of the NSAID and the local anesthetic in the mixture should be unchanged,i.e., theresulting compound should have the same weight percentages as those of the individualNSAID and local anesthetic.

HPLC analysis of the weight percents of lidocaine free base (23.434 g) and diclofenacfree acid (29.615 g) were 44% and 56% respectively in the mixture. However, the HPLCanalysis of the diclofenac salt of lidocaine demonstrated weight percents of the lidocaineportion and the diclofenac portion as 43.2% and 57.4% respectively, indicating that thediclofenac salt of lidocaine differed from a mixture of lidocaine and diclofenac. In otherwords, a new compound, which was physically and chemically different from its parentcompounds, lidocaine and diclofenac, was formed.

EXPERIMENTAL EXAMPLE 2Differential scanning calorimetry (DSC) Analysis of A Diclofenac Salt of Lidocaine Made ByLidocaine Free Base-Diclofenac Free Acid

Lidocaine free base, diclofenac free acid, and diclofenac salt of lidocaine prepared bythe methods described in the present invention were analyzed by DSC. As shown in Figure 1,the free base of lidocaine had an onset temperature at 66.87°C. Its endothermal maximumof melting was at 67.93°C.

As shown in Figure 2, the free acid of diclofenac had an onset temperature at178.12°C. Its endothermal maximum of melting was at 178.99°C.

The thermogram as shown in Figure 3 represented the diclofenac salt of lidocaineprepared by the method described in Example 4 (i.e., by dissolving the lidocaine free baseand diclofenac free acid in acetone followed by evaporation of the acetone). This diclofenacsalt of lidocaine had an onset temperature of 96.0°C and an endothermal maximum ofmelting at 99.71 °C, which were significantly different from those of the lidocaine free basealone or the diclofenac free acid alone.

Also, the thermogram as shown in Figure 4 represented the diclofenac salt oflidocaine prepared by the method described in Example 3 (i.e., by dissolving the lidocainefree base and diclofenac free acid in isopropyl alcohol followed by evaporation of theisopropyl alcohol). The diclofenac salt of lidocaine prepared by this method demonstrated anonset temperature of 95.02°C and an endothermal maximum of melting at 101.82°C, whichwere similar to the onset temperature of 96.0°C and endothermal maximum of melting at99.71°C shown in the diclofenac salt of lidocaine of Example 3. Also, similar to the DSCthermogram of Figure 3, the DSC pattern of the diclofenac salt of lidocaine as shown in Figure 4 was distinctively different from that of the lidocaine free base alone or diclofenacfree acid alone.

Finally, as shown in Figure 5, which represented a thermogram of DSC where thediclofenac salt of lidocaine was prepared by Example 1 (i.e., by dissolving the lidocaine freebase and diclofenac free acid in alcohol followed by removing the alcohol by evaporation).This diclofenac salt of lidocaine of Example 1 showed an onset temperature of 93.16°C andan endothermal maximum of melting at 101.49°C, which were very similar to the data shownin Figures 3 and 4. This finding suggested that the diclofenac salt of lidocaine prepared bydifferent solvents demonstrated similar melting properties and were distinctively differentfrom both the lidocaine free base alone or diclofenac free acid alone.

If the diclofenac salt of lidocaine was simply a combination of the compounds itoriginated, the DSC spectrum should show two separate endothermal melting peakscorresponding to the enthermal melting peaks of the lidocaine alone and the diclofenac alone.However, based on the findings in Figures 3-5, only one single melting peak in the DSCspectrum was found in the diclofenac salt of lidocaine. Also, the melting peak of thediclofenac salt of lidocaine ranged from (99.71°C [Figure 3] to 101.82°C [Figure 4]) wassignificant different from that of either the lidocaine alone [67.93°C] or the diclofenac alone[178.99°C]. This supported the finding that the diclofenac salt of lidocaine was not a simplemixture of the lidocaine free base and the diclofenac free acid.

EXPERIMENTAL EXAMPLE 3Thermogravimetric (TGA) Analysis of A Diclofenac Salt of Lidocaine Made By LidocaineFree Base-Diclofenac Free Acid

Lidocaine free base, diclofenac free acid, and the diclofenac salt of lidocaineprepared by the methods described in the present invention were analyzed by TGA.

As shown in Figure 6, the profile of weight loss versus temperature of the free base oflidocaine base in TGA analysis showed that at 250°C, the % of the remaining weight of thefree base of lidocaine was less than 0.1%.

As shown in Figure 7, the profile of weight loss versus temperature of free acid ofdiclofenac in TGA analysis showed that at 250°C, the % of the remaining weight of the freeacid of diclofenac was about 35.33%.

However, as shown in Figure 8, the TGA profile of weight loss versus temperature ofthe diclofenac salt of lidocaine showed that at 250°C, the % of the remaining weight wasabout 53.05%. The diclofenac salt of lidocaine was prepared by dissolving the lidocaine freebase and diclofenac free acid in acetone, followed by removal of the acetone by naturalevaporation.

Also as shown in Figure 9, the TGA profile of weight loss versus temperature of thediclofenac salt of lidocaine showed that at 250°C, the % of the remaining weight was about37.40%. The diclofenac salt of lidocaine was prepared by dissolving the lidocaine free baseand diclofenac free acid in acetone, followed by removal of the acetone by reduced-pressureor vacuum condensation.

The results of the TGA study indicated that the weight loss versus temperature profileof the diclofenac salt of lidocaine were distinctively different from that of the free baselidocaine but more similar to that of the free acid diclofenac. The results also indicated thatdifferent solvent removal methods might contribute to the production of the diclofenac salt oflidocaine with slightly different TGA profile.

EXPERIMENTAL EXAMPLE 4FTIR Analysis of ofA Diclofenac Salt of Lidocaine Made By Lidocaine Free BaseAnd Diclofenac Free Acid

Infrared spectroscopy (IR) has long been used in the evaluation of chemicalcompounds. Fourier Transform Infrared Spectroscopy (FTIR) has been used to identify andevaluate organic and inorganic materials or compounds. Using FTIR, spectral data iscollected and converted from an interference pattern to a spectrum. The system provides forsubtractive elimination of background spectra, such that particular chemical compounds canbe identified by a molecular "fingerprint."

In the present studies, diclofenac free acid, lidocaine free base, a mixture of lidocainefree base and diclofenac free acid (without solvent dissolution or pulverization), and adiclofenac salt of lidocaine according to Example 1 (supra) were analyzed using FTIR. Theresults were shown in Figures 10-13.

Figure 10 shows the IR spectrum of diclofenac free acid using FTIR. There were 5peaks identified in the diclofenac free acid IR spectrum which were unique to diclofenac.The wavelengths of these 5 peaks were 773.83 cm^-1, 784.57 cm^-1, 1302.05 cm^-1, 1501.69cm^-1 and 1889.99 cm^-1.

Figure 11 shows the IR spectrum of lidocaine using FTIR. There were 6 peaksidentified in the lidocaine free base IR spectrum which were unique to diclofenac. Thewavelengths of these 6 peaks were 764.57 cm^-1, 1088.58 cm^-1, 1199.67 cm^-1, 1296.93 cm^-1,1491.45 cm^-1, 1669.99 cm^-1. None of the peaks identified in the diclofenac free acid wereidentical to those found in lidocaine, suggesting that the characteristics of lidocaine anddiclofenac were not common to each other.

Figure 12 shows the IR spectrum of a mixture of equal moles of lidocaine free baseand diclofenac free acid. The mixture was without further pulverization or solventdissolution. As shown in Figure 12, at least 8 peaks, which were 756.46 cm^-1, 778.96 cm^-1,1076.82 cm^-1, 1267.58 cm^-1, 1367.85 cm^-1, 1501.69cm^-1, 1582.93 cm^-1, and 1670.61 cm^-1,were found in Figure 12. Only one peak, i.e., 1501.69 cm^-1 between diclofenac and themixture of lidocaine and diclofenac was identical. There was no identical peak betweenlidocaine and the mixture of lidocaine and diclofenac.

Figure 13 shows the IR spectrum of the diclofenac salt of lidocaine preparedaccording to Example 1 (supra). Seven IR peaks were found in this compound, which were737.98 cm^-1, 1041.11 cm^-1, 1276.48 cm^-1, 1367.85 cm^-1, 1501.69 cm^-1, 1572.69 cm^-1, and1701.32 cm^-1. Only two out of the 7 peaks,i.e., 1367.85 cm^-1 and 1501.69 cm^-1 wereidentical to the mixture of lidocaine and diclofenac (Figure 12), suggesting that thediclofenac salt of lidocaine was chemically and physically different from the mixture oflidocaine free base and diclofenac free acid.

While the invention has been described by way of examples and in terms of thepreferred embodiments, it is to be understood that the invention is not limited to the disclosedembodiments. On the contrary, it is intended to cover various modifications as would beapparent to those skilled in the art. Therefore, the scope of the appended claims should beaccorded the broadest interpretation so as to encompass all such modifications.

Claims (29)

1. A pharmaceutically acceptable salt comprising a diclofenac salt of lidocaine.
2. The pharmaceutically acceptable salt according to claim 1, wherein saiddiclofenac is replaced with a non-diclofenac non-steroidal anti-inflammatory drug (NSAID);said NSAID being not a salicylic acid derivative; and/or wherein said lidocaine is replacedwith a non-lidocaine local anesthetic.
3. The pharmaceutically acceptable salt according to claim 2, wherein saidNSAID is one selected from the group consisting of etodolac, ketorolac, bromfenac,ibuprofen, fenoprofen, fluriboprofen, ketoprofen, naproxen, suprofen, meclofenamate,mefenamic acid, piroxicam, meloxicam, indomethacin, sulindac, phenylbutazone,oxyphenbutazone, tolmetin, and celecoxib.
4. The pharmaceutically acceptable salt according to claim 3, wherein saidNSAID is ketorolac.
5. The pharmaceutically acceptable salt according to claim 2, wherein said localanesthetic agent is one selected from the group consisting of butacaine, chloroprocaine,cocaine, cyclomethycaine, hexyclaine, procaine, proparacaine, propoxycaine, tetracaine,benzocaine, bupivacaine, dibucaine, etidocaine, lidocaine, mepivacaine, ropivacaine,prilocaine, dyclonine, and pramoxine.
6. A method for making the pharmaceutically acceptable salt according to claim1, comprising:

   dissolving a lidocaine and a diclofenac in a solvent to form a drug mixture;

   removing said solvent from said drug mixture to form said pharmaceuticallyacceptable salt.
7. The method according to claim 6, wherein said lidocaine and said diclofenacare dissolved in said solvent respectively.
8. The method according to claim 6, wherein said lidocaine and said diclofenacare mixed together prior to dissolution in said solvent.
9. The method according to claim 6, wherein said lidocaine is lidocaine free baseor lidocaine-HCl.
10. The method according to claim 6, wherein said diclofenac is diclofenac freeacid, sodium diclofenac, potassium diclofenac, or diethylamine diclofenac.
11. The method according to claim 6, wherein said lidocaine is replaced with afree base or salt of a non-lidocaine local anesthetic agent; and/or said didofenac is replacedwith a free acid or salt of a non-diclofenac non-steroidal anti-inflammatory drug (NSAID);wherein said NSAID is not a salicylic acid derivative.
12. The method according to claim 11, wherein said local anesthetic agent is oneselected from the group consisting of butacaine, chloroprocaine, cocaine, cyclomethycaine,hexyclaine, procaine, proparacaine, propoxycaine, tetracaine, benzocaine, bupivacaine,dibucaine, etidocaine, mepivacaine, ropivacaine, prilocaine, dyclonine, and pramoxine.
13. The method according to claim 11, wherein said NSAID is one selected fromthe group consisting of etodolac, ketorolac, bromfenac, ibuprofen, fenoprofen, fluriboprofen,ketoprofen, naproxen, suprofen, meclofenamate, mefenamic acid, piroxicam, meloxicam,indomethacin, sulindac, phenylbutazone, oxyphenbutazone, tolmetin, and celecoxib.
14. The method according to claim 11, wherein said NSAID is ketorolac.
15. The method according to claim 11, wherein said solvent is at least oneselected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, toluene, chloroform, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methylene chlorideand acetonitrile.
16. The method according to claim 6, wherein said solvent is removed by naturalevaporation, vacuum condensation, or drying under nitrogen.
17. A method for making the pharmaceutically acceptable salt according to claim1, comprising:

    mixing a lidocaine and a diclofenac to form a drug mixture;

    pulverizing said drug mixture by a physical-mechanical means to form saidpharmaceutically acceptable salt.
18. The method according to claim 17, wherein said lidocaine is lidocaine-HCl,sodium diclofenac, potassium diclofenac, or diethylamine diclofenac.
19. The method according to claim 17, wherein said lidocaine is replaced with afree base or salt of a non-lidocaine local anesthetic agent; and/or said diclofenac is replacedwith a free acid or salt of a non-diclofenac non-steroidal anti-inflammatory drug (NSAID);wherein said NSAID is not a salicylic acid derivative.
20. The method according to claim 19, wherein said local anesthetic agent is oneselected from the group consisting of butacaine, chloroprocaine, cocaine, cyclomethycaine,hexyclaine, procaine, proparacaine, propoxycaine, tetracaine, benzocaine, bupivacaine,dibucaine, etidocaine, mepivacaine, ropivacaine, prilocaine, dyclonine, and pramoxine.
21. The method according to claim 19, wherein said NSAID is one selected fromthe group consisting of etodolac, ketorolac, bromfenac, ibuprofen, fenoprofen, fluriboprofen,ketoprofen, naproxen, suprofen, meclofenamate, mefenamic acid, piroxicam, meloxicam,indomethacin, sulindac, phenylbutazone, oxyphenbutazone, tolmetin, and celecoxib.
22. A pharmaceutical formulation comprising the pharmaceutically acceptablesalt of claim 1 and a pharmaceutically acceptable carrier.
23. The pharmaceutical formulation according to claim 22, wherein saidpharmaceutical formulation is for topical treatment.
24. The pharmaceutical formulation according to claim 23, wherein saidpharmaceutical formulation for topical treatment is in the form of solution, gel, emugel,cream, ointment, lotion, transdermal patch, or eye drop.
25. The pharmaceutical formulation according to claim 22, wherein saidpharmaceutical formulation is for parenteral injection.
26. A method for treating patients with localized pain comprising topicallytreating said patients with an effective amount of the pharmaceutical formulation accordingto claim 23.
27. The method according to claim 26, wherein said localized pain is muscle pain,joint pain, pain associated with herpes infection, and wound pain.
28. A method for treating patients with localized pain comprising parenterallyadministering an effective amount of the pharmaceutical formulation according to claim 22.
29. The method according to claim 28, wherein said localized pain is muscle pain,joint pain, pain associated with herpes infection, and wound pain.

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